Oral nonpeptide HRS-7535 significantly reduces HbA1c by up to 1.82% in Type 2 Diabetes patients

Current Type 2 Diabetes (T2DM) management often relies on injectable glucagon-like peptide-1 receptor agonists (GLP-1 RAs), which, despite their efficacy, face limitations in patient adherence due to injection burden. The development of oral small-molecule GLP-1R agonists represents a critical advancement, offering a more convenient administration route. This approach aims to provide comparable glycemic control and weight benefits while improving patient compliance and expanding access to effective GLP-1R pathway modulation for individuals with T2DM.

This 16-week, phase 2, double-blind, placebo-controlled randomized clinical trial enrolled 194 adults (18-75 years) with Type 2 Diabetes and HbA1c levels between 7.5% and 11.0%, who were inadequately controlled on stable metformin therapy. Participants were randomized (1:1:1:1:1) to once-daily oral HRS-7535 at doses of 15 mg, 30 mg, 60 mg, or 90 mg, or matching placebo. The 60 mg and 90 mg groups utilized dose-escalation regimens. The primary endpoint was the change in HbA1c level from baseline to week 16, with secondary outcomes including changes in fasting plasma glucose, 2-hour postprandial glucose, and body weight.

At week 16, all HRS-7535 dose groups demonstrated statistically significant reductions in HbA1c compared to placebo (all P < .001). The mean HbA1c changes from baseline were: -1.19% (95% CI, -1.54% to -0.84%) for 15 mg, -1.59% (95% CI, -1.94% to -1.24%) for 30 mg, -1.82% (95% CI, -2.16% to -1.48%) for 60 mg, and -1.64% (95% CI, -1.97% to -1.30%) for 90 mg. In contrast, the placebo group showed a mean HbA1c change of -0.25% (95% CI, -0.60% to 0.09%). Placebo-adjusted differences ranged from -0.94% (95% CI, -1.43% to -0.45%) to -1.57% (95% CI, -2.05% to -1.08%).

The 60 mg dose of HRS-7535 achieved the largest HbA1c reduction of -1.82%, indicating robust glycemic control. A significant proportion of patients achieved HbA1c levels less than 7.0% across the HRS-7535 groups. The safety profile was consistent with known GLP-1R agonists, with gastrointestinal adverse events being the most common.